tbuckley/cabot-search huggingface dataset:
Atlantoaxial Dislocation in Down's Syndrome
Authors: Burr H. Curtis
Journal: JAMA (1968)

An increased atlantoodontoid interval is frequently observed in asymptomatic patients with Down's syndrome (mongolism) and severe neurologic complications can occur. Symptomatic atlantoaxial dislocations developed in two such patients. Conditions in both patients were relieved by surgical stabilization of the first and second cervical vertebrae.
Extensive plasma proteomic profiling revealed receptor activator of nuclear factor kappa-Β ligand (RANKL) as emerging biomarker of nivolumab clinical benefit in patients with metastatic renal cell carcinoma
Authors: Sonia Simonetti, Michele Iuliani, Marco Stellato, Silvia Cavaliere, Bruno Vincenzi, Giuseppe Tonini, Daniele Santini, Francesco Pantano
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background The advent of immune checkpoint inhibitors (ICIs) have led to a paradigm change in the management of metastatic renal cell carcinoma (mRCC), nevertheless, the benefit of treatment is confined to a limited proportion of patients. Therefore, the identification of predictive biomarkers for response to ICIs represents an unmet clinical need. Here, we performed a large-scale plasma proteomic profile of patients with mRCC, treated with nivolumab, to identify soluble molecules potentially associated with clinical benefit. Methods We analyzed the levels of 507 soluble molecules in the pretreatment plasma of 16 patients with mRCC (discovery set) who received nivolumab therapy as a single agent. The ELISA assay was performed to confirm the protein level of candidate biomarkers associated to clinical benefit in 15 patients with mRCC (validation set). Survival curves of complete cohort were estimated by the Kaplan-Meier method and compared with the log-rank test. Results Out of 507 screened molecules, 135 factors were selected as expressed above background and 12 of them were significantly overexpressed in patients who did not benefit from treatment (non-responders (NR)) compared with responders (R) group. After multiplicity adjustment, receptor activator of nuclear factor kappa-Β ligand (RANKL) was the only molecule that retained the statistical significance (false discovery rate: 0.023). RANKL overexpression in NR patients was confirmed both in discovery (median NR: 528 pg/mL vs median R: 288 pg/mL, p=0.011) and validation set (median NR: 440 pg/mL vs median R: 253 pg/mL, p&lt;0.001). Considering the complete cohort of patients (discovery+validation set), significantly higher RANKL levels were found in patients who primarily progressed from treatment compared with those who had a partial response (p=0.003) or stable disease (p=0.006). Moreover, patients with low RANKL levels had significant improvements in progression-free survival (median 14.0 months vs 3.4 months, p=0.004) and overall survival (median not reached vs 30.1 months, p=0.003). Conclusions Our exploratory study suggests RANKL as a novel independent biomarker of response and survival in patients with mRCC treated with nivolumab.
FBW7-mediated ubiquitination and destruction of PD-1 protein primes sensitivity to anti-PD-1 immunotherapy in non-small cell lung cancer
Authors: Jiaxin Liu, Lingyun Wei, Nan Hu, Dong Wang, Juan Ni, Sha Zhang, Hongbing Liu, Tangfeng Lv, Jie Yin, Mingxiang Ye, Yong Song
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Activation of the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) pathway has been extensively described as a pivotal mechanism to escape immune surveillance and elicits suppressive effect on antitumor immunity. Blockade of the PD-1/PD-L1 interaction by checkpoint inhibitors has been shown to result in tumor shrinkage and prolong patient survival. However, regulatory machinery for PD-1/PD-L1 expression is largely unknown. Methods We used bioinformatic tools and biochemical methods to investigate the significance of F-box and WD repeat domain containing 7 (FBW7) in regulating PD-1 protein stability. By generating a panel of FBW7 and PD-1 encoding plasmids, we expressed FBW7 and PD-1 or their mutants to performed immunoprecipitation and immunoblotting assays. The efficacy of cotargeting FBW7 to enhance antitumor immunity was evaluated in C57BL/6J mice. These laboratory findings were further validated in tumor samples obtained from patients with non-small cell lung cancer (NSCLC). Results We identified FBW7 as a E3 ubiquitin ligase for PD-1 protein, in which FBW7 promotes the K48-linked polyubiquitination of PD-1 protein at Lys233 residue. Cotargeting FBW7 accelerates PD-1 protein degradation and enhances antitumor immunity in vivo. Moreover, we demonstrated that cyclin-dependent kinase 1-mediated phosphorylation of Ser261 residue primes PD-1 protein nucleus translocation and binding with FBW7. Higher expression of FBW7 characterizes a ‘hot’ tumor microenvironment and confers more favorable responses to PD-1 blockade therapy. Conclusions This study highlights the critical role of FBW7 in determining PD-1 protein stability. FBW7 ubiquitinates PD-1 in a phosphorylation-dependent manner, as a consequence, leading to PD-1 protein degradation and cytotoxic lymphocytes infiltrating the tumor microenvironment. Screening FBW7 status would predict clinical response to anti-PD-1 immunotherapy in patients with NSCLC, and targeting FBW7 is a promising strategy to enhance antitumor immunity.
Generation and<i>in vivo</i>validation of an IL-12 fusion protein based on a novel anti-human FAP monoclonal antibody
Authors: Lisa Nadal, Frederik Peissert, Abdullah Elsayed, Tobias Weiss, Thomas Look, Michael Weller, Geny Piro, Carmine Carbone, Giampaolo Tortora, Mattia Matasci, Nicholas Favalli, Riccardo Corbellari, Cesare Di Nitto, Eleonora Prodi, Chiara Libbra, Simone Galeazzi, Claudiopietro Carotenuto, Cornelia Halin, Emanuele Puca, Dario Neri, Roberto De Luca
Journal: Journal for ImmunoTherapy of Cancer (2022)

In this study, we describe the generation of a fully human monoclonal antibody (named '7NP2') targeting human fibroblast activation protein (FAP), an antigen expressed in the microenvironment of different types of solid neoplasms.7NP2 was isolated from a synthetic antibody phage display library and was improved by one round of mutagenesis-based affinity maturation. The tumor recognition properties of the antibody were validated by immunofluorescence procedures performed on cancer biopsies from human patients. A fusion protein consisting of the 7NP2 antibody linked to interleukin (IL)-12 was generated and the anticancer activity of the murine surrogate product (named mIL12-7NP2) was evaluated in mouse models. Furthermore, the safety of the fully human product (named IL12-7NP2) was evaluated in Cynomolgus monkeys.Biodistribution analysis in tumor-bearing mice confirmed the ability of the product to selectively localize to solid tumors while sparing healthy organs. Encouraged by these results, therapy studies were conducted in vivo, showing a potent antitumor activity in immunocompetent and immunodeficient mouse models of cancer, both as single agent and in combination with immune checkpoint inhibitors. The fully human product was tolerated when administered to non-human primates.The results obtained in this work provided a rationale for future clinical translation activities using IL12-7NP2.
Errors in Byline
Authors: Marco Fiore
Journal: JAMA Surgery (2022)

Multicenter Selective Lymphadenectomy Trials Study Group; Jessica S. Crystal, MD; John F. Thompson, MD; John Hyngstrom, MD; Corrado Caracò, MD; Jonathan S. Zager, MD; Tiina Jahkola, MD; Tawnya L. Bowles, MD; Elisabetta Pennacchioli, MD; Peter D. Beitsch, MD; Harald J. Hoekstra, MD, PhD; Marc Moncrieff, MBBS, MD; Christian Ingvar, MD; Alexander van Akkooi, MD, PhD; Michael S. Sabel, MD; Edward A. Levine, MD; Doreen Agnese, MD; Michael Henderson, MD; Reinhard Dummer, MD; Rogerio I. Neves, MD; Carlo Riccardo Rossi, MD; John M. Kane III, MD; Steven Trocha, MD; Frances Wright, MD; David R. Byrd, MD; Maurice Matter, MD; Eddy C. Hsueh, MD; Alastair MacKenzie-Ross, MD; Mark Kelley, MD; Patrick Terheyden, MD; Tara L. Huston, MD; Jeffrey D. Wayne, MD; Heather Neuman, MD; B. Mark Smithers, MBBS; Charlotte E. Ariyan, MD, PhD; Darius Desai, MD; Jeffrey E. Gershenwald, MD; Shlomo Schneebaum, MD; Anja Gesierich, MD; Lisa K. Jacobs, MD; James M. Lewis, MD; Kelly M. McMasters, MD, PhD; Cristina O’Donoghue, MD; Andre van der Westhuizen, MD; Armando Sardi, MD; Richard Barth, MD; Robert Barone, MD; J. Greg McKinnon, MD; Craig L. Slingluff, MD; Jeffrey M. Farma, MD; Erwin Schultz, MD; Randall P. Scheri, MD; Sergi Vidal-Sicart, MD; Manuel Molina, MD; Alessandro A. E. Testori, MD; Leland J. Foshag, MD; Lisa Van Kreuningen, MS; He-Jing Wang, MD; Myung-Shin Sim, MS, PhD; Richard A. Scolyer, MD; David E. Elashoff, PhD; Alistair J. Cochran, MD; Mark B. Faries, MD
Tumor-associated macrophage-specific CD155 contributes to M2-phenotype transition, immunosuppression, and tumor progression in colorectal cancer
Authors: Xudong Zhu, Rongpu Liang, Tianyun Lan, Dongbing Ding, Shengxin Huang, Jun Shao, Zongheng Zheng, Tufeng Chen, Yong Huang, Jianpei Liu, Janak L Pathak, Hongbo Wei, Bo Wei
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Onco-immunogenic molecule CD155 is overexpressed in various tumor microenvironments (TME) including in colorectal cancer (CRC). Tumor-associated macrophages (TAMs) are the most abundant immune cells in CRC TME and play a vital role in CRC progression and metastasis. Most studies have focused on investigating the role of CRC cell-specific CD155 on CRC progression, while the contribution of TAMs-specific CD155 is still unknown. Here, we sought to investigate the expression pattern of CD155 in CRC TAMs and its role in tumor immunity and progression. Methods CD155 expression patterns in CRC TAMs and macrophages in paratumor or adjacent normal tissue were analyzed in 50 patients with CRC using flow cytometry and in 141 patients with CRC using immunohistochemistry. The correlation of CD155 expression level in TAMs with M1 and M2 phenotypic transition was analyzed. The role of macrophage-specific CD155 in CRC progression and tumor immune response was investigated in vitro and in vivo. We further analyzed the effect of CRC cells on the regulation of CD155 expression in macrophages. Results CRC TAMs from clinical samples showed robustly higher expression of CD155 than macrophages from paratumor and adjacent normal tissues. The CD155 expression level was higher in TAMs of CRC at III/IV stages compared with the I/II stages and was negatively associated with the survival of patients with CRC. CD155 + TAMs showed an M2 phenotype and higher expression of interleukin (IL)-10 and transforming growth factor (TGF)-β. CD155 + macrophages promoted CRC cell migration, invasion, and tumor growth supporting the findings from the clinical tissue analysis. This effect was mainly regulated by TGF-β-induced STAT3 activation-mediated release of matrix metalloproteinases (MMP)2 and MMP9 in CRC cells. CD155 –⁄– bone marrow transplantation in wild-type mice, as well as CD155– macrophages treatment, promoted the antitumor immune response in the mice ectopic CRC model. Additionally, CRC cells released IL-4 to trigger CD155 expression in macrophages indicating the regulatory role of CRC cells in the development of CD155 + TAMs. Conclusions These findings indicated that CD155 + TAMs are responsible for the M2-phenotype transition, immunosuppression, and tumor progression in CRC. The specific localization of CD155 + TAMs in CRC tissue could turn into a potential therapeutic target for CRC treatment.
Reply
Authors: Heejoon Jang, Yun Bin Lee, Juneyoung Lee
Journal: Hepatology (2022)

We appreciate Dr. Lai's interest and comments on our article.[1] In our current study, we demonstrated an association between aspirin use and the risk of hepatocellular carcinoma (HCC) using a Korean nationwide population‐based cohort of patients with chronic hepatitis B. Immortal time bias, which can often mislead to an overestimation of the effect size, can be involved in most observational studies evaluating drug effects.[2] Immortal time refers to a follow‐up period during which outcomes could not have occurred.[3,4] It typically occurs when there is a gap between cohort entry and an initial exposure to the drug, in which the span of time is inevitably event‐free and thus “immortal.” In our study, because the index date of the aspirin‐treated group was set to the 180th day after the date of the first aspirin prescription, immortal time could not have intervened. If the index date of a patient who was prescribed aspirin for 90 days had been set to the first prescription date, those 90 days would correspond to an immortal time, during which the patient necessarily had to be event‐free. In Case A, we believe the period after the patient has been exposed to aspirin for 90 days, which Dr. Lai suggests to be an “immortal time,” should be regarded only as an “unexposed period” because an event can occur at any time point during that period. In addition, in Case B, Dr. Lai considered the period between stopping and resuming aspirin an immortal time. Because an effective treatment duration of aspirin for HCC chemoprevention remains unclear, we adopted a selection criterion of 90 consecutive days of aspirin use to define aspirin users.[5] Discontinuation or resumption of aspirin after a sufficient exposure to aspirin (≥90 consecutive days) was not considered in the analysis. Thus, the period that Dr. Lai designated as immortal time in Case B cannot be called immoral time in the same context as aforementioned. CONFLICT OF INTEREST Yun Bin Lee received grants from Samjin Pharmaceuticals and Yuhan Pharmaceuticals.
Restoration of p53 activity via intracellular protein delivery sensitizes triple negative breast cancer to anti-PD-1 immunotherapy
Authors: Zaofeng Yang, Jacquelyne Ka-Li Sun, Marianne M Lee, Michael K Chan
Journal: Journal for ImmunoTherapy of Cancer (2022)

Although immune checkpoint inhibitors (ICIs) have been shown to yield promising therapeutic outcomes in a small subset of patients with triple negative breast cancer (TNBC), the majority of patients either do not respond or subsequently develop resistance. Recent studies have revealed the critical role of TP53 gene in cancer immunology. Loss or mutation of p53 in cancer cells has been found to promote their immune escape. Given the high mutation frequency of TP53 in TNBC cells, restoration of p53 function could be a potential strategy to overcome their resistance to anti-programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) therapy. Herein, we have assessed the use of Pos3Aa crystal-based platform to mediate the intracellular delivery of p53 protein to restore p53 activity in p53 null tumors and consequently augment anti-PD-1 activity.The efficiency of Pos3Aa-p53 crystals in delivering p53 protein was evaluated using confocal imaging, immunofluorescence staining, flow cytometry and RNA-seq. The ability of Pos3Aa-p53 crystals to remodel tumor microenvironment was investigated by examining the markers of immunogenic cell death (ICD) and the expression of PD-L1, indoleamine 2,3-dioxygenase 1, tryptophan 2,3-dioxygenase 2 and type I interferon (IFN). Finally, both unilateral and bilateral 4T1 tumor mouse models were utilized to assess the efficacy of Pos3Aa-p53 crystal-mediated p53 restoration in enhancing the antitumor activity of ICIs. T cells in tumor tissues and spleens were analyzed, and the in vivo biosafety of the Pos3Aa-p53 crystal/anti-PD-1 antibody combination was also evaluated.Delivery of p53 protein into p53-null TNBC 4T1 cells via Pos3Aa-p53 crystals restored the p53 activity, and therefore led to the induction of ICD, activation of type I IFN signaling and upregulation of PD-L1 expression. Pos3Aa-p53 crystals significantly enhanced T cell infiltration and activation in 4T1 tumors, thereby sensitizing them to anti-PD-1 therapy. The combination of Pos3Aa-p53 crystals with anti-PD-1 antibody also induced a systemic antitumor immunity resulting in the inhibition of distal tumor growth with minimal toxicity.This study validates that p53 restoration can be an effective approach to overcome ICI resistance and demonstrates that intracellular delivery of p53 protein can be an efficient, safe and potentially universal strategy to restore p53 activity in tumors carrying TP53 mutation.
Treatment for Appendicitis
Authors: Sophie Ryan, Giordano Perin, Saba Balasubramanian
Journal: JAMA Surgery (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
Association Between Inflammatory Bowel Disease and Both Psoriasis and Psoriatic Arthritis
Authors: Dennis Freuer, Jakob Linseisen, Christa Meisinger
Journal: JAMA Dermatology (2022)

Importance Psoriasis, psoriatic arthritis, and inflammatory bowel disease, ie, Crohn disease and ulcerative colitis, are chronic systemic immune-mediated disorders affecting an increasing proportion of adults and children worldwide. Observational studies have suggested an association between inflammatory bowel disease and psoriasis and vice versa. So far, however, it remains unclear whether and in which direction causal relationships exist. Objective To investigate the association between inflammatory bowel disease, particularly Crohn disease and ulcerative colitis, and psoriasis or psoriatic arthritis. Design, Setting, and Participants A bidirectional 2-sample mendelian randomization study was conducted using summary statistics from genome-wide association studies including up to 463 372 European individuals. Total and direct effects were derived performing an iterative radial and robust inverse-variance weighted method within the univariable and multivariable mendelian randomization setting, respectively. Causal estimates were verified using a validation inflammatory bowel disease sample, a series of pleiotropy-robust mendelian randomization methods, and sensitivity analyses based on a PhenoScanner search in conjunction with network analysis. Data analysis was performed from April to May 2022. Main Outcomes and Measures Inflammatory bowel disease, Crohn disease, ulcerative colitis, psoriasis, and psoriatic arthritis were used as both exposures and outcomes. Results The European samples included 12 882 cases of inflammatory bowel disease and 5621 cases of psoriasis. The proportion of women ranged between 48% and 56%. Genetically predicted inflammatory bowel disease was associated with higher risk of psoriasis (pooled odds ratio [OR], 1.10; 95% CI, 1.05-1.15; P &amp;amp;lt; .001) and psoriatic arthritis (pooled OR, 1.10; 95% CI, 1.04-1.18; P = .003). In contrast with ulcerative colitis, the Crohn disease subentity was associated with psoriasis (OR, 1.16; 95% CI, 1.12-1.20; P &amp;amp;lt; .001) and psoriatic arthritis (OR, 1.13; 95% CI, 1.06-1.20; P &amp;amp;lt; .001). Regarding the reverse directions, no notable associations could be found. Conclusions and Relevance Findings of this mendelian randomization study support a causal effect between inflammatory bowel disease and psoriasis as well as psoriatic arthritis, but not vice versa. It seems that especially Crohn disease and not ulcerative colitis is responsible for the causal effect of inflammatory bowel disease on both psoriasis outcomes. These findings have implications for the management of inflammatory bowel disease and psoriasis in clinical practice.
JAMA Cardiology
Authors: Patrick O'gara, Marc Sabatine, Clyde Boston, Ann Yancy, Michael Pencina, Carolina North, Robert Harrington, Adrian Hernandez, Mhs Durham, North Carolina, Ajay Kirtane, New York, Roxana Mehran, Pradeep Natarajan, Kristen Boston, Seattle Patton, Washington Udelson, Sadiya Khan, Gregg Fonarow, Los Angeles, Sharlene Day, Laine Thomas, Akhil Narang, Julia Getts, Eugene Braunwald, Judith Hochman, Donald Lloyd-Jones, Scm Chicago, Michael Parmacek, Daniel Simon, Sidney Smith, Chapel Hill, Carolina Douglas, E Vaughan, Myron Weisfeldt, Maryland Douglas, P Zipes, Paul Armstrong, Shinya Goto, Peter Liu, Renato Lopes, Carolina Prabhakaran, Hugh Watkins, Harvey White, Habib Yacoub, Frs London, Phil Fontanarosa, Annette Flanagin, Robert Golub, Michael Berkwits, Brenda Gregoline, Tracy Frey, Iris Lo, Kevin Brown, Bernadette Hromin, Erin Keenan, Rebecca Langley, Kris Simmons, Connie Manno, Sara Billings, Doug Brandt, Timothy Gray, Peter Olson, Juliet Orellana, Paul Ruich, Kirby Snell, Judith Ahlers, Stephanie Beckmeyer, Dawn Bielawski, Jane Calayag, Jan Clavey, Mary Coerver-Connolly, Amy Eutsey, Paul Jaworski, Ruth Kaufman, Laura King, Martha Lentz, Jenny Mackay, Nellie Mcgrew, Charon Pierson, Lori Ryan, Thressa Smith, Divya Sreekumar, Donna Thordsen, Christine Tilles, Emma Underdown, Cara Wallace, Becki Weiss, Christina West, Caroline Woods, Erin Kato, Jacob Kendall-Taylor, Monica Mungle, Lenette Gardner-Gullens, Fanny Brown, Anna Bukowski, Lee Calibeo, Jordan Faber, Andrew Given, Tosca Hall, Kenneth Otani, Caroline Sietmann, Angelia Waltower, Jesse Mcquarters, Elena Guobyte, Daniel Morrow, Shelly Steff, Deanna Bellandi, Jim Michalski, Eman Aly, Reuben Rios, Mary Ferkaluk, Jonathan Laxamana, Sidra Bonner, Heather Hsu, Andrew Ibrahim, Karen Bucher, Andy Rekito, Nick Reback, Lohitha Kethu, Marla Erson, Joseph Thornton, Thomas Easley, Brian Shields, Karen Adams-Taylor, Paul Gee, Monica Smith, Julie Burton, Ronna Hewitt, Mary Sieck, Geneine Someren, Jamaal Vargas, Content Systems, Mike Bujewski, Nathan Mitre, Digital Production, Regina Brownlee, Amanda Camino, Brenda Chandler-Grayer, Emily Dunn, Amy Evers, Maleeka Holden, Teri Hutchison, Dan Knowles, Joshua Lampinen, Natalie Marsh, Patricia Panek, Marla Seidell, La Son, Diggs Sledge, Julian Graphics, Joe Amft, Jonathan Chala, Maria Duda, Fred Furtner, Carolyn Hall, Maria Kowalkowski, Joy Farrell, Maria Giannini, Sasha Grossman, Kate Lander, Judith Literskis, Teresa Omiotek, Michael Ryder, James Madara, Kirsten Bibbins-Domingo, Robert Bonow
Journal: JAMA Cardiology (2022)

science, and evidence-based health policy.Health equity, especially when supported by original science, is a leading editorial priority.